Approximately 3% of the world's population is infected with hepatitis C virus (HCV). Although new therapies have improved the rates of sustained response, the majority of patients fail to respond to antiviral treatment, remaining at risk for disease progression. In the current proposal, because viral clearance is likely mediated by the efficient coordination of various components of the immune response, we will explore the relative contribution of natural killer (NK) cells and dendritic cells (DCs) as well as the regulation of HCV-specific CD8+ T cell expansion and proliferation by various innate cytokines (e.g., type I IFN, IL-15). In order to elucidate the nature and kinetics of the innate and adaptive immune responses and how they might exert control over viral replication in the treatment setting, we propose three specific aims to be accomplished in cooperation with the NIDDK-sponsored Virahep-C clinical study of HCV resistance to antiviral therapy. Aim 1. To evaluate how NK cell responses contribute to the control of HCV In patients undergoing antiviral therapy. We hypothesize that patients who demonstrate relatively diminished NK cell activity at baseline will have a greater chance of resistance to antiviral therapy;moreover, we will examine how NK responses are modified by therapy. Aim 2. Determine how the frequency and function of myeloid (mDC) and plasmacytoid dendritic cells (pDC) correlate with response to antiviral therapy. Viral kinetic responses (e.g., null vs. fast response) will be correlated with frequency of DCs and level of IFN-a and IL-12 production. We will also examine in vitro and directly ex vivo the immunoregulatory cross-talk between DCs and NK cells. Aim 3. To precisely define the mechanisms underlying enhanced proliferation of HCV-specific CD8+ T cells with successful antiviral therapy. The maturation defects and functional impairment of HCV-specific CTL responses appear to be reversible with antiviral therapy, and our preliminary data suggest that innate cytokines (e.g., IL-15) may be critical. This information will enhance our understanding of the pathogenesis of this common disease, will provide biomarkers for identifying patients more likely to respond or not respond to antiviral therapy earlier in their course and, hopefully, will lead to development of novel immunotherapeutic approaches.